We showed that the two pairs of histone acetyltransferases (HATs), GCN5 (Kat2a)/PCAF (Kat2b) and CBP/p300, are specifically required for H3K9 acetylation (H3K9ac) and H3K18/27 acetylation (H3K18/27ac), respectively, in cells. Further, CBP/p300 and their HAT activities are essential, while GCN5/PCAF and associated H3K9ac are dispensable, for ligand-induced nuclear receptor target gene expression. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylation in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in nuclear receptor target gene expression (Jin Q. et al., EMBO J, 2011). Further we showed that GCN5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous interferon-beta and the vast majority of active genes in fibroblasts. Instead, GCN5/PCAF repress interferon-beta production and innate antiviral immunity in cells in a HAT-independent and non-transcriptional manner (EMBO Rep 2014). We are investigating the role of H3K36 methylation in regulating PPAR target gene expression and adipogenesis. Using GR as the model system to understand epigenomic regulation of nuclear receptor target gene activation, we have found that GR activates expression of early adipogenic genes by recruiting H3K27 acetyltransferase CBP/p300 to promote activation of C/EBPbeta-primed enhancers. In addition, using conditional knockout mice and derived preadipocytes, we show that surprisingly, endogenous GR and two early adipogenic TFs, Krox20 and KLF4, are largely dispensable for adipogenesis in culture and adipose tissue development in mice. These results challenge the existing model on transcriptional regulation in the early phase of adipogenesis and highlight the need of studying adipogenesis in vivo (Park YK. et al., MCB, 2017a and 2017b).